Treatment of HIV-infected individuals is one of the most pressing biomedical problems of recent times. A promising new therapy has emerged as an important method for preventing or inhibiting the rapid proliferation of the virus in human tissue. HIV-protease inhibitors block a key enzymatic pathway in the virus resulting in substantially decreased viral loads, which slows the steady decay of the immune system and its resulting deleterious effects on human health. The HIV-protease inhibitor nelfinavir mesylate of formula 7
has been shown to be an effective treatment for HIV-infected individuals. Nelfinavir mesylate is disclosed in U.S. Pat. No. 5,484,926, issued Jan. 16, 1996. This patent is entirely incorporated by reference into this patent application.
The present inventors have discovered useful intermediate compounds that can be used in several reaction schemes to make nelfinavir mesylate. The present inventors also have discovered new methods for making nelfinavir mesylate from the free base nelfinavir of formula 4: 
The nelfinavir free base also is disclosed in U.S. Pat. No. 5,484,926.
It is an object of this invention to provide compounds and intermediates useful for making HIV-protease inhibitors and methods of making HIV-protease inhibitors. Such inhibitors are useful for treating HIV-infected individuals.
In a first aspect, the invention relates to compounds of formula 3: 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6,
wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9
wherein each R3 is independently an alkyl group, a cydoalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen, with the proviso that when R1 is xe2x80x94CH3, X cannot be xe2x80x94OCH3 or xe2x80x94OH, and when R1 is CH3C(O)xe2x80x94, X cannot be xe2x80x94OH;
or a pharmaceutically acceptable salt or solvate thereof.
In various preferred embodiments of the invention, R1 is xe2x80x94C(O)CH3 and/or X is a halogen, preferably, Cl.
In another aspect, the invention relates to compounds of formula 2: 
wherein R1 is a C2 to C8 alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula 8
wherein R2 is a C2 to C8 alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or a pharmaceutically acceptable salt or solvate thereof.
This invention further relates to methods for making the compounds of formulae 2 and 3. In a method for making a compound of formula 2: 
a compound according to formula 1, shown below, 
is reacted under suitable and sufficient conditions to add an R1 protecting group and form a compound of formula 2. In this instance, R1 is a C2 to C8 alkyl group; a cycloalkyl group; a heterocycloalkyl group; an aryl group; a heteroaryl group; or a group of formula 8
wherein R2 is a C2 to C8 alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or R1 is a group of formula 9
wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group.
This invention includes a method of making a compound according to formula 3
This method includes adding, under suitable and sufficient conditions, a suitable protecting group R1 and a leaving group X to a compound of formula 1
In this instance, R1 is alkyl, cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or R1 is a group of formula 9
wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7, is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen, with the proviso that when R1 is xe2x80x94CH3, X cannot be xe2x80x94OCH3 or xe2x80x94OH, and when R1 is CH3C(O)xe2x80x94, X cannot be xe2x80x94OH. As noted above, in certain embodiments, R1 is xe2x80x94C(O)CH3 and/or X is a halogen, preferably, Cl.
A compound according to formula 3, as defined above, also can be made from a compound of formula 2. The reaction proceeds by adding a suitable leaving group X to the compound of formula 2. In this instance, formula 2 is as defined below: 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9
wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group. Additionally, in this instance, X is defined as OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen. In this method, when R1 is xe2x80x94CH3, X cannot be xe2x80x94OCH3 or xe2x80x94OH, and when R1 is CH3C(O)xe2x80x94, X cannot be xe2x80x94OH.
This invention further relates to methods for making HIV-protease inhibitors. One HIV-protease inhibitor produced by a method according to this invention is a compound of formula 4, illustrated below: 
In this method, a compound of formula 3
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen,
is reacted under suitable and sufficient conditions to form the compound of formula 4. Again, for one preferred embodiment of this process, the variable R1 represents xe2x80x94C(O)CH3 and/or the variable X represents Cl.
The compound according to formula 4, identified above, also can be prepared by deprotecting a compound of formula 5
and reacting with it, under sufficient conditions, a compound of formula 3. In this instance, the compound according to formula 3 is 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9
wherein each R3 independently is an alkyl group, a cydoalkyl group, a heterocydoalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen;. OSO2R8, wherein R1 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen.
In another embodiment of this invention, a compound of formula 4, as identified above, can be prepared by combining a compound of formula 3: 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen,
with a compound of formula 6
under conditions sufficient and suitable to obtain the compound of formula 4.
This invention further relates to methods of making a compound of formula 7. In one embodiment, the compound of formula 7
is produced by converting a compound of formula 4
under sufficient and suitable conditions to the compound of formula 7. In this method, the conversion of the compound of formula 4 to the compound of formula 7 takes place by:
(a) contacting the compound of formula 4 with an organic solvent;
(b) contacting the compound of formula 4 with methanesulfonic acid under conditions sufficient to form a compound of formula 7; and
(c) spray drying the compound of formula 7. In a more specific embodiment of this method, the organic solvent is ethanol.
In another method for making a compound of formula 7 from a compound of formula 4, the following procedure is followed:
(a) the compound of formula 4, a suitable solvent, and methanesulfonic acid are combined to form the compound of formula 7, the compound of formula 7 being dissolved in solution;
(b) a first antisolvent is added to the solution containing the compound of formula 7;
(c) the compound of formula 7 and the first antisolvent are agitated together to form a product having a solid phase and a liquid phase; and
(d) the product is filtered and washed with a second antisolvent, the second antisolvent being the same as or different from the first antisolvent, to obtain a solid final product according to formula 7. After the solid final product is washed, it can be dred by any appropriate method or means. Tetrahydrofuran can be used as the solvent, and diethylether can be used as at least one antisolvent, preferably at least the first antisolvent.
This invention also relates to a method of making a compound according to formula 4 (as defined above) from a compound according to formula 2. In this method, a compound according to formula 2 is reacted under sufficient and suitable conditions to form the compound of formula 4. In this instance, the compound of formula 2 is defined as follows: 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; a group of formula 8
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group.
Yet another embodiment of this invention relates to a method of making a compound of formula 7, defined above. In this method, a compound according to formula 5
is deprotected. Then, the deprotected compound of formula 5 is reacted, under sufficient and suitable conditions, with a compound of formula 3. Formula 3, in this instance, is defined as follows: 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen. The reaction of compounds 3 and 5 produces a compound of formula 4, described above. The compound according to formula 4 is then converted to the compound of formula 7, for example, by one of the methods described above.
This invention relates to compounds and intermediates useful for making HIV-protease inhibitors, methods of making the compounds and intermediates, and methods of making HIV-protease inhibitors.
As mentioned above, one aspect of this invention relates to compounds that are useful (e.g., as starting materials or intermediates) for making HIV-protease inhibitors. One such group of compounds are identified in this application by formula 3, shown below: 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; a group of formula 8
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, Oxe2x80x94R6 (wherein R6 is an alkyl group, an aralkyl group, or an aryl group); a group of formula 9
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; or a group of formula 10
wherein R4 and each R6 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7 (wherein R7 is alkyl or aryl); halogen; pseudohalogen, including azide, cyanide, isocyanate and isothiocyanate; OSO2R8 (wherein R8 is alkyl or aryl); heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic, including hydroxysuccinimide or hydroxybenzotriazole ester, bonded through the oxygen, with the proviso that when R1 is xe2x80x94CH3, X cannot be xe2x80x94OCH3 or xe2x80x94OH, and when R1 is CH3C(O)xe2x80x94, X cannot be xe2x80x94OH; and to pharmaceutically acceptable salts and solvates thereof. Preferably X is a halogen, particularly, Cl.
The present invention also is directed to novel compounds of formula 2
wherein R1 is a C2 to C8 alkyl group; a cycloalkyl group; a heterocycloalkyl group; an aryl group; a heteroaryl group; a group of formula 8
wherein R2 is a C2 to C8 alkyl group, a cycloalkyl group, a heterocycloalkyl group, Oxe2x80x94R6 (wherein R6 is an alkyl group, an aralkyl group, or an aryl group); a group of formula 9
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; or a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and to pharmaceutically acceptable salts and solvates thereof.
When R1 is a group of formula 8 where R2 is alkyl, R1 can be, for example, acetate, propanoate, butanoate, pivaloate, or any related alkyl ester or mixed carbonate with a group such as benzyl . Other examples of R1 groups where R1 is a group of formula 8 include esters of aromatic and heteroaromatic acids, such as benzoate, substituted benzoate, 1- or 2-naphthoate or substituted 1- or 2-naphthoate, or a substituted 5- or 6-membered heteroaromatic ester. Examples of R1 groups where R1 is an alkyl include methyl, substituted methyl, ethyl, propyl, and butyl. Examples of R1 when R1 is a silyl ether of formula 9 include trimethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, triphenylsilyl, and silyl ethers where the alkyl groups R3 are some combination of simple alkyl and aryl groups. Examples of R1 where R1 is part of an acetal or ketal of formula 10 include acetonide, cyclohexylidene ketal, benzylidene acetal, 2-methoxyethoxyethyl acetal, and related acetals and ketals where R4 and R5 are alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In certain preferred compounds of formulae 2 and 3, and in pharmaceutically acceptable salts and solvates thereof, R1 is xe2x80x94C(O)CH3; alternatively expressed, R2 in a group of formula 8 is CH3.
The present invention is further directed to, various methods of making compounds of formulae 2, 3, 4 (nelfinavir free base), and 7 (nelfinavir mesylate), as described above. Other methods of preparing nelfinavir free base using compounds of formulae 2 and 3 are described in U.S. patent application Ser. No. 08/708,607, filed Sep. 5, 1996, which application also is entirely incorporated herein by reference. Other methods of using compounds of Formulae 2 and 3 are disclosed in JP 95-248183 and JP 95-248184, each of which is entirely incorporated herein by reference.
As used in the present application, the following definitions apply:
The term xe2x80x9calkylxe2x80x9d as used herein refers to substituted or unsubstituted, straight or branched chain groups, preferably, having one to eight, more preferably having one to six, and most preferably having from one to four carbon atoms. The term xe2x80x9cC1-C6 alkylxe2x80x9d represents a straight or branched alkyl chain having from one to six carbon atoms. Exemplary C1-C6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, isohexyl, and the like. The term xe2x80x9cC1-C6 alkylxe2x80x9d includes within its definition the term xe2x80x9cC1-C4 alkyl.xe2x80x9d
The term xe2x80x9ccycloalkylxe2x80x9d represents a substituted or unsubstituted, saturated or partially saturated, mono- or poly-carbocyclic ring, preferably having 5-14 ring carbon atoms. Exemplary cycloalkyls include monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Exemplary cycloalkyls are C5-C7 cycloalkyls, which are saturated hydrocarbon ring structures containing from five to seven carbon atoms.
The term xe2x80x9carylxe2x80x9d as used herein refers to an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, or 18 carbon ring atoms, which may be unsubstituted or substituted, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluoren-2-yl, indan-5-yl, and the like.
The term xe2x80x9chalogenxe2x80x9d represents chlorine, fluorine, bromine, or iodine. The term xe2x80x9chaloxe2x80x9d represents chloro, fluoro, bromo, or iodo.
The term xe2x80x9ccarbocyclexe2x80x9d represents a substituted or unsubstituted aromatic or a saturated or a partially saturated 5-14 membered monocyclic or polycyclic ring, which is substituted or unsubstituted, such as a 5- to 7-membered monocyclic or 7- to 10-membered bicyclic ring, wherein all the ring members are carbon atoms.
A xe2x80x9cheterocycloalkyl groupxe2x80x9d is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing 3, 4, 5, 6, 7. 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, and which includes 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the radical is unsubstituted or substituted, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted. Illustrative examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl, 1,5,9-triazacyclododecyl, and the like.
A xe2x80x9cheteroaryl groupxe2x80x9d is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be unsubstituted or substituted, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted. Illustrative examples of heteroaryl groups include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, and phenoxazinyl.
The term xe2x80x9cacylxe2x80x9d represents L6C(O)L4, wherein L6 is a single bond, xe2x80x94O, or xe2x80x94N, and further wherein L4 is preferably alkyl, amino, hydroxyl, alkoxyl, or hydrogen. The alkyl, amino, and alkoxyl groups optionally can be substituted. An exemplary acyl is a C1-C4 alkoxycarbonyl, which is a straight or branched alkoxyl chain having from one to four carbon atoms attached to a carbonyl moiety. Exemplary C1-C4 alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, and the like. Another exemplary acyl is a carboxy wherein L6 is a single bond and L4 is alkoxyl, hydrogen, or hydroxyl. A further exemplary acyl is Nxe2x80x94(C1-C4)alkylcarbamoyl (L6 is a single bond and L4 is an amino), which is a straight or branched alkyl chain having from one to four carbon atoms attached to the nitrogen atom of a carbamoyl moiety. Exemplary Nxe2x80x94(C1-C4)alkylcarbamoyl groups include N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, and N-t-butylcarbamoyl, and the like. Yet another exemplary acyl is N,N-di(C1-C4)alkylcarbamoyl, which has two straight or branched alkyl chains, each having from one to four carbon atoms attached to the nitrogen atom of a carbamoyl moiety. Exemplary N,N-di(C1-C4)alkylcarbamoyl groups include N,N-dimethylcarbamoyl, N,N-,ethylmethylcarbamoyl, N,N-methylpropylcarbamoyl, N,N-ethylisopropylcarbamoyl, N,N-butylmethylcarbamoyl, N,N-sec-butylethylcarbamoyl, and the like.
Suitable protecting groups are recognizable to those skilled in the art. Examples of suitable protecting groups can be found in T. Green and P. Wuts, Protective Groups in Organic Synthesis (2d ed. 1991), which is incorporated herein by reference.
The term xe2x80x9caralkylxe2x80x9d as used herein refers to any substituted or unsubstituted group that is sp3 hybridized at the point of attachment that also possesses an aromatic ring or rings with that group.
The term xe2x80x9cpseudohalogenxe2x80x9d as used herein refers to azides, cyanides, isocyanates, and isothiocyanates.
The term xe2x80x9cN-hydroxyheterocyclicxe2x80x9d as used herein refers to substituted and unsubstituted groups having an oxygen atom at the point of attachment that is also bonded to the nitrogen of a nitrogen heterocyclic ring or ring system. Examples of such groups include: 
The term xe2x80x9calkyl esterxe2x80x9d as used herein refers to ester groups where the group attached to the esterilying oxygen is an alkyl group.
The term xe2x80x9cmixed carbonatexe2x80x9d as used herein refers to compounds containing the functional group 
where Ra and Rb independently are alkyl, aryl, or aralkyl groups.
The term xe2x80x9cester of an aromatic or heteroaromatic acidxe2x80x9d as used herein refers to carboxylic acids wherein the carboxyl group is attached directly to a substituted or unsubstituted aromatic or heteroaromatic ring, such as benzoic acid or 2-furoic acid.
The term xe2x80x9cDABCOxe2x80x9d as used herein refers to the reagent 1,4-diazabicyclo[2.2.2]octane.
The term xe2x80x9cDBNxe2x80x9d as used herein refers to the reagent 1,5-diazabicyclo[4.3.0]non-5-ene.
The term xe2x80x9cDBUxe2x80x9d as used herein refers to the reagent 1,8-diazabicyclo[5.4.0]undec-7-ene.
The term xe2x80x9csilyl etherxe2x80x9d as used herein refers to the group: 
wherein Rc, Rd, and Re independently are alkyl, aryl or aralkyl groups.
The term xe2x80x9cperfluoralkanesulfonatexe2x80x9d as used herein refers to alkane sulfonate esters wherein one or more of the hydrogens are replaced by fluorines.
The term xe2x80x9cvinyl alkyl etherxe2x80x9d as used herein refers to ether groups where an alkyl group and a substituted or unsubstituted olefin-containing group are bonded to the ethereal oxygen, and the olefin-containing group is bonded to the ethereal oxygen at one of the doubly-bonded carbons.
The term xe2x80x9carylsufonic acidxe2x80x9d as used herein refers to groups of formula: 
wherein Ar is a substituted or unsubstituted aromatic ring.
The term xe2x80x9cleaving groupxe2x80x9d as used herein refers to any group that departs from a molecule in a substitution reaction by breakage of a bond. Examples of leaving groups include, but are not limited to, halides, arenesulfonates, alkylsulfonates, and triflates.
The term xe2x80x9carenesulfonatexe2x80x9d as used herein refers to any substituted or unsubstituted group that is an ester of an arylsulfonic acid.
The term xe2x80x9calkyl or aryl carbodiimidesxe2x80x9d as used herein refers to any reagent of formula Rfxe2x80x94Nxe2x95x90Cxe2x95x90Nxe2x80x94Rg, wherein Rf and Rg independently are aryl, alkyl, or aralkyl.
The term xe2x80x9cDMFxe2x80x9d as used herein refers to the solvent N,N-dimethylformamide.
The term xe2x80x9cNMPxe2x80x9d as used herein refers to the solvent N-methyl-2-pyrolidinone.
The term xe2x80x9cTHFxe2x80x9d as used herein refers to the solvent tetrahydrofuran.
The term xe2x80x9calkyl thiolatesxe2x80x9d as used herein refers to substituted or unsubstituted compounds that are metal salts of alkanethiols.
The term xe2x80x9ctrialkylsilyl halidexe2x80x9d as used herein refers to compounds having a silicon that holds 3 alkyl groups that may be the same or different.
The term xe2x80x9chydrogenolysisxe2x80x9d as used herein refers to a reaction in which a single bond is broken and hydrogens become bonded to the atom""s that were formerly bonded.
Examples of substituents for alkyl and aryl include mercapto, thioether, nitro (NO2), amino, aryloxyl, halogen, hydroxyl, alkoxyl, and acyl, as well as aryl, cycloalkyl, and saturated and partially saturated heterocycles. Examples of substituents for cycloalkyl include those listed above for alkyl and aryl, as well as aryl and alkyl.
Exemplary substituted aryls include a phenyl or naphthyl ring substituted with one or more substituents, preferably one to three substituents independently selected from halo; hydroxy; morpholino(C1-C4)alkoxy carbonyl; pyridyl (C1-C4)alkoxycarbonyl; halo (C1-C4)alkyl; C1-C4 alkyl; C1-C4alkoxy; carboxy; C1-C4 alkoxycarbonyl; carbamoyl; Nxe2x80x94(C1-C4)alkylcarbamoyl; amino; C1-C4alkylamino; di(C1-C4)alkylamino; or a group of the formula xe2x80x94(CH2)axe2x80x94R7 where a is 1, 2, 3, or 4, and R7 is hydroxy, C1-C4 alkoxy, carboxy, C1-C4 alkoxycarbonyl, amino, carbamoyl, C1-C4 alkylamino, or di(C1-C4)alkylamino.
Another substituted alkyl is halo(C1-C4)alkyl, which represents a straight or branched alkyl chain having from one to four carbon atoms with 1-3 halogen atoms attached to it. Exemplary halo(C1-C4)alkyl groups include chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl, and the like.
Another substituted alkyl is hydroxy(C1-C4)alkyl, which represents a straight or branched alkyl chain having from one to four carbon atoms with a hydroxy group attached to it. Exemplary hydroxy(C1-C4)alkyl groups include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyisopropyl, 4-hydroxybutyl, and the like.
Yet another substituted alkyl is C1-C4 alkylthio(C1-C4)alkyl, which is a straight or branched C1-C4 alkyl group with a C1-C4 alkylthio group attached to it. Exemplary C1-C4 alkylthio(C1-C4)alkyl groups include methylthiomethyl, ethylthiomethyl, propylthiopropyl, sec-butylthiomethyl, and the like.
Yet another exemplary substituted alkyl is heterocycle(C1-C4)alkyl, which is a straight or branched alkyl chain having from one to four carbon atoms with a heterocycle attached to it. Exemplary heterocycle(C1-C4)alkyls include pyrrolylmethyl, quinolinylmethyl, 1-indolylethyl, 2-furylethyl, 3-thien-2-ylpropyl, 1-imidazolylisopropyl, 4-thiazolylbutyl, and the like.
Yet another substituted alkyl is aryl(C1-C4)alkyl, which is a straight or branched alkyl chain having from one to four carbon atoms with an aryl group attached to it. Exemplary aryl(C1-C4)alkyl groups include phenylmethyl, 2-phenylethyl, 3-naphthyl-propyl, 1-naphthylisopropyl, 4-phenylbutyl, and the like.
The heterocycloalkyls and heteroaryls can, for example, be substituted with 1, 2, or 3 substituents independently selected from halo; halo(C1-C4)alkyl; C1-C4 alkyl; C1-C4 alkoxy; carboxy; C1-C4 alkoxycarbonyl; carbamoyl; Nxe2x80x94(C1-C4)alkylcarbamoyl; amino; C1-C4alkylamino; di(C1-C4)alkylamino; or a group having the structure xe2x80x94(CH2)axe2x80x94R7 where a is 1, 2, 3, or 4, and R7 is hydroxy, C1-C4 alkoxy, carboxy, C1-C4 alkoxycarbonyl, amino, carbamoyl, C1-C4alkylamino, or di(C1-C4)alkylamino.
Examples of substituted heterocycloalkyls include, but are not limited to, 3-N-t-butyl carboxamide decahydroisoquinolinyl and 6-N-t-butyl carboxamide octahydro-thieno[3,2-c]pyridinyl. Examples of substituted heteroaryls include, but are not limited to, 3-methylimidazolyl, 3-methoxypyridyl, 4-chloroquinolinyl, 4-aminothiazolyl, 8-methylquinolinyl, 6-chloroquinoxalinyl, 3-ethylpyridyl, 6-methoxybenzimidazolyl, 4-hydroxyfuryl, 4-methylisoquinolinyl, 6,8-dibromoquinolinyl, 4,8-dimethylnaphthyl, 2-methyl-1,2,3,4-tetrahydroisoquinolinyl, N-methyl-quinolin-2-yl, 2-t-butoxycarbonyl-1,2,3,4-isoquinolin-7-yl, and the like.
A xe2x80x9cpharmaceutically acceptable solvatexe2x80x9d is intended to mean a solvate that retains the biological effectiveness and properties of the biologically active components of compounds of formulae 2 and 3.
Examples of pharmaceutically acceptable solvates include, but are not limited to, compounds prepared using water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
In the case of solid formulations, it is understood that the inventive compounds can exist in different forms, such as stable and metastable crystalline forms and isotropic and amorphous forms, all of which are intended to be within the scope of the present invention.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is intended to mean those salts that retain the biological effectiveness and properties of the free acids and bases and that are not biologically or otherwise undesirable.
Examples of pharmaceutically acceptable salts include, butare not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.
If the inventive compound is a base, the desired salt can be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid; hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid; and the like, or with an organic acid, such as acetic acid; maleic acid; succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; pyranosidyl acids such as glucuronic acid and galacturonic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such a p-toluenesulfonic acid or ethanesulfonic acid; or the like.
If the inventive compound is an acid, the desired salt can be prepared by any suitable method known in the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; and cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
All inventive compounds that contain at least one chiral center can exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the present invention. Preferably, the compounds of the present invention are used in a form that contains at least 90% of a single isomer (80% enantiomeric or diastereomeric excess), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.). Compounds identified herein as single stereoisomers are meant to describe compounds used in a form that contains at least 90% of a single isomer.
The inventive compounds can be prepared by the novel methods of the present invention, which are described in detail below. Additionally, these compounds can be used to prepare nelfinavir free base and nelfinavir mesylate according to the inventive methods described below.
A reaction scheme for the conversion of 3-hydroxy-2-methylbenzoic acid derivatives to nelfinavir free base is as follows: 
The acid 1 is commercially available from Lancaster Labs and Sugai Chemical Industries, Ltd. in Japan. The acid 1 also can be obtained according to the procedure described in U.S. Pat. No. 5,484,926, for the Preparation of 9C.
When R1 is an acyl group or an ester of an aromatic or heteroaromatic acid, R1 can be installed onto 3-hydroxy-2-methylbenzoic acid (Step 1) using the corresponding acyl halides or anhydrides in typical organic solvents for these types of reactions, such as halogenated solvents, ethers, and hydrocarbons accompanied by a base. Such bases typically are inorganic bases, such as metal hydroxides, bicarbonates, and carbonates, or organic bases, such as amines like triethylamine, diethylamine, diethyl isopropylamine, DABCO, or related di- or trialkylamines, as well as amidine bases like DBU and DBN. These reactions typically are run anywhere from below room temperature to approximately 100xc2x0 C. Alternatively, the esterification can be catalyzed by acids such as sulfuric acid when used in conjunction with anhydrides.
When R1 is an ether group, R1 can be installed using conditions that utilize the corresponding R1 group bonded to a leaving group, which is subsequently displaced. These reactions generally are performed in most common organic solvents such as THF, diethyl ether, dioxane, methyl t-butyl ether, or other ethers; esters such as ethyl, methyl, and isopropyl acetate; halogenated solvents such as halogenated methanes and ethanes, chlorobenzene, and other halogenated benzenes; nitriles such acetonitrile and propionitrile; lower alcohols such as ethanol, isopropanol, t-butanol, and related alcohols; and polarorganic solvents such as dimethyiformamide, dimethylsulfoxide, N-methyl-2-pyrolidinone, and related amide-containing solvents. A base usually accompanies such a process. The bases typically are inorganic, such as metal hydroxides, bicarbonates, and carbonates, or organic, such as amines like triethylamine, diethylamine, diethyl isopropylamine, DABCO, or related di- or trialkylamines, as well as amidine bases like DBU and DBN. These reactions typically are run anywhere from below room temperature to approximately 100xc2x0 C.
When R1 is a silyl ether, it can be installed using the corresponding silyl halides or perfluoralkanesulfonates in most common organic solvents such as THF, diethyl ether, dioxane, methyl t-butyl ether, or other ethers; esters such as ethyl, methyl, and isopropyl acetate; halogenated solvents such as halogenated methanes and ethanes, chlorobenzene, and other halogenated benzenes; nitriles such acetonitrile and propionitrile; and polar organic solvents such as dimethylformamide, N-methyl-2-pyrolidinone, and related amide-containing solvents. A base usually accompanies such a process. The bases typically are inorganic bases, such as metal hydroxides, bicarbonates, and carbonates, or organic bases, such as amines like triethylamine, diethylamine, diethyl isopropylamine, DABCO, or related di- or trialkylamines, as well as amidine bases like DBU and DBN.
When R1 is part of an acetal or ketal group, R1 can be installed by alkylation with the corresponding xcex1-haloether in a manner similar to other alkyl halides as described above. Alternatively, acid-promoted addition of 3-hydroxy-2-methylbenzoic acid to the corresponding vinyl alkyl ether can be used. These reactions are promoted by both organic acids (such as p-toluenesulfonic and related alkyl and arylsulfonic acids, trifluoroacetic acid and related organic carboxylic acids with a pK of less than 2) and inorganic acids (such as sulfuric, hydrochloric, phosphoric, and nitric acids).
The group X is installed in Step 2 by reaction of the carboxylic acid derivative 2. The acyl halides of formula 3 can be prepared using inorganic halogenating agents such as thionyl chloride or bromide, phosphorus trichloride or -bromide, phosphorus pentachloride or bromide, or organic agents such as oxalyl chloride or trichlorisocyanuric acid. This process can be catalyzed by DMF or a related alkyl amide.
Esters of formula 3 can be prepared in a variety of ways starting from the acid chloride (compounds of formula 3) by combination with the desired alcohol in the presence of an organic or inorganic base stated previously. Alternatively, the ester can be produced by acid-promoted esterification in the presence of the desired alcohol. The sulfonates usually are made by reaction of the carboxylic acid derivatives (compounds of formula 2) with alkyl or arylsulfonyl chlorides in the presence of an organic amine base such as triethylamine in a non-polar solvent at temperatures below 0xc2x0 C. The pseudohalogen derivatives generally are made from the acid halides (compounds of formula 3) by reaction with inorganic pseudohalide in the presence of a base. The heteroaryl derivatives (compounds of formula 2) also are made from the acid halides of formula 3 utilizing the specific heteroaryl compound in the presence of an amine base in a non-polar solvent. The N-hydroxyheterocyclic derivatives can be made from the acid halides of formula 3 as above and can also be generated using alkyl or aryl carbodiimides and an amine base as condensing agents.
The coupling of compound 3 to amine 6 (Step 3) can be carried out in a variety of ways, depending on the identity of X. When a free acid is used (X=OH), the coupling can be performed using carbodiimide based methods utilizing any of the common reagents of this class including dicyclohexylcarbodiimide or related dialkylcarbodiimides, EDC (salts of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) or related water soluble reagents along with an organic amine base in polar organic solvents such as dioxane, DMF, NMP, and acetonitrile in the presence of an N-hydroxyheterocyclic including hydroxysuccinimide or N-hydroxybenzotrazole ester. When X is a halogen or pseudohalogen, the coupling can be performed in most common organic solvents such as THF; diethyl ether, dioxane, methyl t-butyl ether, or other ethers; acetone, cyclohexanone, methyl isobutylketone and other ketones; esters such as ethyl, methyl, and isopropyl acetate; halogenated solvents such as halogenated methanes and ethanes; chlorobenzene and other halogenated benzenes; nitriles such acetonitrile and propionitrile; lower alcohols such as ethanol, isopropanol, t-butanol, and related alcohols; and polar organic solvents such as dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrolidinone, and related amide-containing solvents. A base frequently is used and can be any of a number of inorganic bases (such as metal hydroxides, bicarbonates, and carbonates) or organic bases (such as amines like. triethylamine, diethylamine, diethyl isopropylamine, DABCO, or related di- or trialkylamines, as well as amidine bases like DBU and DBN).
Protecting group removal is accomplished using any of the standard methods for deprotecting a particular class of protecting group. Esters and carbonates usually are removed with aqueous or alcoholic solutions of inorganic bases, such as metal hydroxides, carbonates, and bicarbonates, at ambient temperatures up to 100xc2x0 C. Ethers are deprotected using boron- based Lewis acidic compounds such as BBr3 and BCl3, alkyl thiolates, or trialkylsilyl halides. Either ether or carbonate protecting groups that contain benzyl groups bonded to heteroatoms can be removed by hydrogenolysis with a palladium or platinum catalyst. Acetal-based protecting groups can be removed under aqueous or alcoholic acidic conditions, promoted by Lewis acids such as transition metal halides or halides of the Group 3 metals, or by protic organic acids (such as p-toluenesulfonic and related alkyl and arylsulfonic acids, trifluoroacetic acid and related organic carboxylic acids with a pK of less than 2) and inorganic acids (such as sulfuric, hydrochloric, phosphoric, and nitric acids). Silylether protecting group removal can be accomplished by aqueous or alcoholic acid or base or by fluoride ion promoted desilylation by use of inorganic fluoride sources such as potassium or cesium fluoride or by tetralkylammonium fluoride salts.
Nelfinavir mesylate can be prepared from 3-acetoxy-2-methylbenzoyl chloride (acid chloride). The acid chloride can be prepared from the corresponding 3-hydroxy-2-methylbenzoic acid in the following two step procedure: 
In the production of the acid chloride, the acid 1 is converted to the acetoxy acid (a compound of formula 2), which is treated with thionyl chloride to give 3-acetoxy-2-methylbenzoyl chloride in good yield.
The acid chloride then can be coupled to the amine 6 under classical conditions resulting in the production of nelfinavir free base as follows: 
The acid chloride is treated with the amine 6 in the presence of triethylamine in THF at ambient temperature for 30 minutes followed by an aqueous basic hydrolysis of the acetate group to give nelfinavir free base. The free base can be converted to nelfinavir mesylate by methods described in more detail below.